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Article: Management of Cytomegalovirus Infections in the Era of the Novel Antiviral Players, Letermovir and Maribavir.

Piret, Jocelyne / Boivin, Guy

Infectious disease reports

2024 Volume 16, Issue 1, Page(s) 65–82

Abstract: Cytomegalovirus (CMV) infections may increase morbidity and mortality in immunocompromised patients. Until recently, standard antiviral drugs against CMV were limited to viral DNA polymerase inhibitors (val)ganciclovir, foscarnet and cidofovir with a ... ...

Abstract	Cytomegalovirus (CMV) infections may increase morbidity and mortality in immunocompromised patients. Until recently, standard antiviral drugs against CMV were limited to viral DNA polymerase inhibitors (val)ganciclovir, foscarnet and cidofovir with a risk for cross-resistance. These drugs may also cause serious side effects. This narrative review provides an update on new antiviral agents that were approved for the prevention and treatment of CMV infections in transplant recipients. Letermovir was approved in 2017 for CMV prophylaxis in CMV-seropositive adults who received an allogeneic hematopoietic stem cell transplant. Maribavir followed four years later, with an indication in the treatment of adult and pediatric transplant patients with refractory/resistant CMV disease. The target of letermovir is the CMV terminase complex (constituted of pUL56, pUL89 and pUL51 subunits). Letermovir prevents the cleavage of viral DNA and its packaging into capsids. Maribavir is a pUL97 kinase inhibitor, which interferes with the assembly of capsids and the egress of virions from the nucleus. Both drugs have activity against most CMV strains resistant to standard drugs and exhibit favorable safety profiles. However, high-level resistance mutations may arise more rapidly in the
Language	English
Publishing date	2024-01-18
Publishing country	Switzerland
Document type	Journal Article ; Review
ISSN	2036-7430
ISSN	2036-7430
DOI	10.3390/idr16010005
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: The impact of trained immunity in respiratory viral infections.

Piret, Jocelyne / Boivin, Guy

Reviews in medical virology

2023 Volume 34, Issue 1, Page(s) e2510

Abstract: Epidemic peaks of respiratory viruses that co-circulate during the winter-spring seasons can be synchronous or asynchronous. The occurrence of temporal patterns in epidemics caused by some respiratory viruses suggests that they could negatively interact ... ...

Abstract	Epidemic peaks of respiratory viruses that co-circulate during the winter-spring seasons can be synchronous or asynchronous. The occurrence of temporal patterns in epidemics caused by some respiratory viruses suggests that they could negatively interact with each other. These negative interactions may result from a programme of innate immune memory, known as trained immunity, which may confer broad protective effects against respiratory viruses. It is suggested that stimulation of innate immune cells by a vaccine or a pathogen could induce their long-term functional reprogramming through an interplay between metabolic and epigenetic changes, which influence the transcriptional response to a secondary challenge. During the coronavirus disease 2019 pandemic, the circulation of most respiratory viruses was prevented by non-pharmacological interventions and then resumed at unusual periods once sanitary measures were lifted. With time, respiratory viruses should find again their own ecological niches. This transition period provides an opportunity to study the interactions between respiratory viruses at the population level.
MeSH term(s)	Humans ; Trained Immunity ; Immunity, Innate ; Viruses ; Vaccines ; COVID-19
Chemical Substances	Vaccines
Language	English
Publishing date	2023-10-13
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	1086043-5
ISSN	1099-1654 ; 1052-9276
ISSN (online)	1099-1654
ISSN	1052-9276
DOI	10.1002/rmv.2510
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Zs.A 3308: Show issues

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Article: Corrigendum: Pandemics throughout history.

Piret, Jocelyne / Boivin, Guy

Frontiers in microbiology

2022 Volume 13, Page(s) 988058

Abstract: This corrects the article DOI: 10.3389/fmicb.2020.631736.]. ...

Abstract	[This corrects the article DOI: 10.3389/fmicb.2020.631736.].
Language	English
Publishing date	2022-09-27
Publishing country	Switzerland
Document type	Published Erratum
ZDB-ID	2587354-4
ISSN	1664-302X
ISSN	1664-302X
DOI	10.3389/fmicb.2022.988058
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Article ; Online: Viral Interference between Respiratory Viruses.

Piret, Jocelyne / Boivin, Guy

Emerging infectious diseases

2022 Volume 28, Issue 2, Page(s) 273–281

Abstract: Multiple respiratory viruses can concurrently or sequentially infect the respiratory tract and lead to virus‒virus interactions. Infection by a first virus could enhance or reduce infection and replication of a second virus, resulting in positive ( ... ...

Abstract	Multiple respiratory viruses can concurrently or sequentially infect the respiratory tract and lead to virus‒virus interactions. Infection by a first virus could enhance or reduce infection and replication of a second virus, resulting in positive (additive or synergistic) or negative (antagonistic) interaction. The concept of viral interference has been demonstrated at the cellular, host, and population levels. The mechanisms involved in viral interference have been evaluated in differentiated airway epithelial cells and in animal models susceptible to the respiratory viruses of interest. A likely mechanism is the interferon response that could confer a temporary nonspecific immunity to the host. During the coronavirus disease pandemic, nonpharmacologic interventions have prevented the circulation of most respiratory viruses. Once the sanitary restrictions are lifted, circulation of seasonal respiratory viruses is expected to resume and will offer the opportunity to study their interactions, notably with severe acute respiratory syndrome coronavirus 2.
MeSH term(s)	Animals ; COVID-19 ; Humans ; Pandemics ; Respiratory Tract Infections/epidemiology ; SARS-CoV-2 ; Viral Interference ; Viruses
Language	English
Publishing date	2022-01-25
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	1380686-5
ISSN	1080-6059 ; 1080-6040
ISSN (online)	1080-6059
ISSN	1080-6040
DOI	10.3201/eid2802.211727
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Zs.A 4778: Show issues

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Article ; Online: Viral Interference between Respiratory Viruses

Jocelyne Piret / Guy Boivin

Emerging Infectious Diseases, Vol 28, Iss 2, Pp 273-

2022 Volume 281

Abstract	Multiple respiratory viruses can concurrently or sequentially infect the respiratory tract and lead to virus‒virus interactions. Infection by a first virus could enhance or reduce infection and replication of a second virus, resulting in positive (additive or synergistic) or negative (antagonistic) interaction. The concept of viral interference has been demonstrated at the cellular, host, and population levels. The mechanisms involved in viral interference have been evaluated in differentiated airway epithelial cells and in animal models susceptible to the respiratory viruses of interest. A likely mechanism is the interferon response that could confer a temporary nonspecific immunity to the host. During the coronavirus disease pandemic, nonpharmacologic interventions have prevented the circulation of most respiratory viruses. Once the sanitary restrictions are lifted, circulation of seasonal respiratory viruses is expected to resume and will offer the opportunity to study their interactions, notably with severe acute respiratory syndrome coronavirus 2.
Keywords	viral interference ; viruses ; respiratory viruses ; respiratory infections ; influenza virus ; respiratory syncytial virus ; Medicine ; R ; Infectious and parasitic diseases ; RC109-216
Language	English
Publishing date	2022-02-01T00:00:00Z
Publisher	Centers for Disease Control and Prevention
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article: Antiviral Drugs Against Herpesviruses.

Piret, Jocelyne / Boivin, Guy

Advances in experimental medicine and biology

2021 Volume 1322, Page(s) 1–30

Abstract: The discovery of the nucleoside analogue, acyclovir, represented a milestone in the management of infections caused by herpes simplex virus and varicella-zoster virus. Ganciclovir, another nucleoside analogue, was then used for the management of systemic ...

Abstract	The discovery of the nucleoside analogue, acyclovir, represented a milestone in the management of infections caused by herpes simplex virus and varicella-zoster virus. Ganciclovir, another nucleoside analogue, was then used for the management of systemic and organ-specific human cytomegalovirus diseases. The pyrophosphate analogue, foscarnet, and the nucleotide analogue, cidofovir, have been approved subsequently and constitute the second-line antiviral drugs. However, the viral DNA polymerase is the ultimate target of all these antiviral agents with a possible emergence of cross-resistance between these drugs. Recently, letermovir that targets the viral terminase complex was approved for the prophylaxis of human cytomegalovirus infections in hematopoietic stem cell transplant recipients. Other viral targets such as the protein kinase and the helicase-primase complex are also evaluated for the development of novel potent inhibitors against herpesviruses.
MeSH term(s)	Antiviral Agents/pharmacology ; Antiviral Agents/therapeutic use ; Cidofovir/pharmacology ; Cytomegalovirus ; Drug Resistance, Viral/genetics ; Humans ; Simplexvirus
Chemical Substances	Antiviral Agents ; Cidofovir (JIL713Q00N)
Language	English
Publishing date	2021-07-13
Publishing country	United States
Document type	Journal Article
ISSN	2214-8019 ; 0065-2598
ISSN (online)	2214-8019
ISSN	0065-2598
DOI	10.1007/978-981-16-0267-2_1
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Article: Pandemics Throughout History.

Piret, Jocelyne / Boivin, Guy

Frontiers in microbiology

2021 Volume 11, Page(s) 631736

Abstract: The emergence and spread of infectious diseases with pandemic potential occurred regularly throughout history. Major pandemics and epidemics such as plague, cholera, flu, severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East ... ...

Abstract	The emergence and spread of infectious diseases with pandemic potential occurred regularly throughout history. Major pandemics and epidemics such as plague, cholera, flu, severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV) have already afflicted humanity. The world is now facing the new coronavirus disease 2019 (COVID-19) pandemic. Many infectious diseases leading to pandemics are caused by zoonotic pathogens that were transmitted to humans due to increased contacts with animals through breeding, hunting and global trade activities. The understanding of the mechanisms of transmission of pathogens to humans allowed the establishment of methods to prevent and control infections. During centuries, implementation of public health measures such as isolation, quarantine and border control helped to contain the spread of infectious diseases and maintain the structure of the society. In the absence of pharmaceutical interventions, these containment methods have still been used nowadays to control COVID-19 pandemic. Global surveillance programs of water-borne pathogens, vector-borne diseases and zoonotic spillovers at the animal-human interface are of prime importance to rapidly detect the emergence of infectious threats. Novel technologies for rapid diagnostic testing, contact tracing, drug repurposing, biomarkers of disease severity as well as new platforms for the development and production of vaccines are needed for an effective response in case of pandemics.
Language	English
Publishing date	2021-01-15
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2587354-4
ISSN	1664-302X
ISSN	1664-302X
DOI	10.3389/fmicb.2020.631736
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Article: DNA polymerases of herpesviruses and their inhibitors.

Piret, Jocelyne / Boivin, Guy

The Enzymes

2021 Volume 50, Page(s) 79–132

Abstract: Human herpesviruses are large double-stranded DNA viruses belonging to the Herpesviridae family. The main characteristics of these viruses are their ability to establish a lifelong latency into the host with a potential to reactivate periodically. ... ...

Abstract	Human herpesviruses are large double-stranded DNA viruses belonging to the Herpesviridae family. The main characteristics of these viruses are their ability to establish a lifelong latency into the host with a potential to reactivate periodically. Primary infections and reactivations with herpesviruses are responsible for a large spectrum of diseases and may result in severe complications in immunocompromised patients. The viral DNA polymerase is a key enzyme in the replicative cycle of herpesviruses, and the target of most antiviral agents (i.e., nucleoside, nucleotide and pyrophosphate analogs). However, long-term prophylaxis and treatment with these antivirals may lead to the emergence of drug-resistant isolates harboring mutations in genes encoding viral enzymes that phosphorylate drugs (nucleoside analogs) and/or DNA polymerases, with potential cross-resistance between the different analogs. Drug resistance mutations mainly arise in conserved regions of the polymerase and exonuclease functional domains of these enzymes. In the polymerase domain, mutations associated with resistance to nucleoside/nucleotide analogs may directly or indirectly affect drug binding or incorporation into the primer strand, or increase the rate of extension of DNA to overcome chain termination. In the exonuclease domain, mutations conferring resistance to nucleoside/nucleotide analogs may reduce the rate of excision of incorporated drug, or continue DNA elongation after drug incorporation without excision. Mutations associated with resistance to pyrophosphate analogs may alter drug binding or the conformational changes of the polymerase domain required for an efficient activity of the enzyme. Novel herpesvirus inhibitors with a potent antiviral activity against drug-resistant isolates are thus needed urgently.
MeSH term(s)	Antiviral Agents/pharmacology ; DNA-Directed DNA Polymerase/genetics ; Herpesviridae/genetics ; Humans ; Nucleosides ; Simplexvirus
Chemical Substances	Antiviral Agents ; Nucleosides ; DNA-Directed DNA Polymerase (EC 2.7.7.7)
Language	English
Publishing date	2021-09-01
Publishing country	United States
Document type	Journal Article
ISSN	0423-2607
ISSN	0423-2607
DOI	10.1016/bs.enz.2021.07.003
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Article ; Online: In vitro activity of letermovir against human cytomegalovirus isolates with different drug susceptibility phenotypes.

Piret, Jocelyne / Goyette, Nathalie / Boivin, Guy

Antiviral research

2022 Volume 202, Page(s) 105328

Abstract: Letermovir (LTV) is approved for the prophylaxis of human cytomegalovirus (HCMV) infection in adult seropositive recipients of an allogeneic hematopoietic stem cell transplant. Here, we report on the in vitro activity of LTV against a large panel of ... ...

Abstract	Letermovir (LTV) is approved for the prophylaxis of human cytomegalovirus (HCMV) infection in adult seropositive recipients of an allogeneic hematopoietic stem cell transplant. Here, we report on the in vitro activity of LTV against a large panel of clinical HCMV isolates and recombinant viruses with different drug susceptibility phenotypes to currently-approved DNA polymerase inhibitors or maribavir. No pre-existing mutations conferring resistance to LTV were detected by Sanger sequencing in clinical HCMV isolates susceptible or resistant to DNA polymerases inhibitors. The susceptibility of LTV against the different recombinant HCMV mutants with amino acid substitutions in the UL97 kinase or in the UL54 DNA polymerase was similar to that of the wild type virus. LTV was also effective against recombinant HCMV harboring UL97 mutations conferring resistance to maribavir.
MeSH term(s)	Acetates ; Antiviral Agents/pharmacology ; Antiviral Agents/therapeutic use ; Cytomegalovirus/genetics ; Cytomegalovirus Infections ; Drug Resistance, Viral/genetics ; Ganciclovir/pharmacology ; Humans ; Mutation ; Phenotype ; Quinazolines
Chemical Substances	Acetates ; Antiviral Agents ; Quinazolines ; letermovir (1H09Y5WO1F) ; Ganciclovir (P9G3CKZ4P5)
Language	English
Publishing date	2022-04-28
Publishing country	Netherlands
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	306628-9
ISSN	1872-9096 ; 0166-3542
ISSN (online)	1872-9096
ISSN	0166-3542
DOI	10.1016/j.antiviral.2022.105328
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Zs.A 1627: Show issues

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Article ; Online: Immunomodulatory Strategies in Herpes Simplex Virus Encephalitis.

Piret, Jocelyne / Boivin, Guy

Clinical microbiology reviews

2020 Volume 33, Issue 2

Abstract: Herpes simplex virus 1 (HSV-1) can be responsible for life-threatening HSV encephalitis (HSE). The mortality rate of patients with HSE who do not receive antiviral treatment is 70%, with most survivors suffering from permanent neurological sequelae. The ... ...

Abstract	Herpes simplex virus 1 (HSV-1) can be responsible for life-threatening HSV encephalitis (HSE). The mortality rate of patients with HSE who do not receive antiviral treatment is 70%, with most survivors suffering from permanent neurological sequelae. The use of intravenous acyclovir together with improved diagnostic technologies such as PCR and magnetic resonance imaging has resulted in a reduction in the mortality rate to close to 20%. However, 70% of surviving patients still do not recover complete neurological functions. Thus, there is an urgent need to develop more effective treatments for a better clinical outcome. It is well recognized that cerebral damage resulting from HSE is caused by viral replication together with an overzealous inflammatory response. Both of these processes constitute potential targets for the development of innovative therapies against HSE. In this review, we discuss recent progress in therapy that may be used to ameliorate the outcome of patients with HSE, with a particular emphasis on immunomodulatory agents. Ideally, the administration of adjunctive immunomodulatory drugs should be initiated during the rise of the inflammatory response, and its duration should be limited in time to reduce undesired effects. This critical time frame should be optimized by the identification of reliable biomarkers of inflammation.
MeSH term(s)	Acyclovir/therapeutic use ; Adrenal Cortex Hormones/therapeutic use ; Animals ; Antiviral Agents/therapeutic use ; Drug Therapy ; Encephalitis, Herpes Simplex/diagnosis ; Encephalitis, Herpes Simplex/immunology ; Encephalitis, Herpes Simplex/therapy ; Genetic Predisposition to Disease ; Humans ; Immunity ; Immunomodulation ; Risk Factors ; Simplexvirus/drug effects ; Treatment Outcome
Chemical Substances	Adrenal Cortex Hormones ; Antiviral Agents ; Acyclovir (X4HES1O11F)
Language	English
Publishing date	2020-02-12
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	645015-5
ISSN	1098-6618 ; 0893-8512
ISSN (online)	1098-6618
ISSN	0893-8512
DOI	10.1128/CMR.00105-19
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Zs.A 2409: Show issues

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